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UC Riverside UC Riverside Previously Published Works Title The biology and total syntheses of bisbenzylisoquinoline alkaloids. Permalink https://escholarship.org/uc/item/67s758hb Journal Organic & biomolecular chemistry, 19(35) ISSN 1477-0520 Authors Nguyen, Viviene K Kou, Kevin GM Publication Date 2021-09-15 DOI 10.1039/d1ob00812a Peer reviewed eScholarship.org Powered by the California Digital Library University of California Please do not adjust margins REVIEW The biology and total syntheses of bisbenzylisoquinoline alkaloids Viviene K. Nguyen, Kevin. G. M. Kou* Received 00th January 20xx, Accepted 00th January 20xx DOI: 10.1039/x0xx00000x This mini-review provides a concise overview of the biosynthetic pathway and pharmacology of the bisbenzylisoquinoline alkaloid (bisBIA) natural poducts. Additional emphasis is given to the methodologies in the total syntheses of both the simpler acyclic diaryl ether dimers and their macrocyclic counterparts bearing two diaryl ether linkages. 1. Introduction and classification The benzylisoquinoline alkaloids (BIAs) represent a family of over 2500 plant natural products that have been used for centuries as analgesics and wound disinfectants.1 Some of the active and biosynthetically-related members, have been exploited in modern medicine, for example, morphine for pain, 2 colchicine for gout, and noscapine for cough and cancer. In Figure 1. Coclaurine (1 and 2) and/or reticuline (3) are the recent years, the pursuit of bisbenzylisoquinoline alkaloids biosynthetic building blocks of the majority of bisBIAs. (bisBIAs), molecules comprising two BIA motifs, is gaining traction. Isolated from the Berberidaceae, Ranunculaceae, their botanical sources as well as spectral and physical data.1-8 Lauraceae and Menispermaceae plant families, these This review highlights the biosynthesis and medicinal compounds can modulate diverse biological functions.3,4 With implications of bisBIAs. Further attention is given to the varied and rich pharmacology and chemistry, the majority of prevailing synthesis strategies for preparing these alkaloids. these alkaloids arise from the condensation of two coclaurine units (1 or 2) while some can arise from the condensation of a coclaurine with reticuline (3, Figure 1).5,6 Based on these 2. Biosynthesis distinctions, bisBIAs are often divided into three major classes: BisBIAs come from a highly conserved biosynthetic 7 bisreticulines, coclaurine-reticulines, and biscoclaurines. pathway.8 Catalyzed by tyrosine decarboxylase, the In all instances, the two benzylisoquinoline moieties are biosynthesis begins with the conversion of amino acid (S)- linked via biphenyl, diphenyl ether, or benzyl phenyl ether tyrosine (4) into 4-hydroxyphenylacetaldehyde (5) and 7 bonds. Aromatic rings with hydroxy, methoxy or dopamine (6, Figure 2).8,9 A Pictet–Spengler transformation methylenedioxy substituents and two chiral centers make up facilitated by the enzyme norcoclaurine synthase combines the key features of bisBIAs. Therefore, a high degree of variation arylacetaldehyde 5 with dopamine (6) to generate (S)- is observed depending on the number of ether linkages, the norcoclaurine. After two successive enzymatic O- and N- sites on the two units at which the linkage originates, the nature methylation steps, the core intermediate N-methylcoclaurine of substitution of the nitrogen atoms, and the degree of (2) is attained that ultimately gives rise to an array of BIAs. unsaturation with regard to the heterocycles. For simple bisBIA derivatives, two N-methylcoclaurine units Currently, over five hundred bisBIAs are known and have are oxidatively dimerized via the P450 enzyme CYP80A1.8,10 since been the subject of several review articles detailing their More complex cyclic bisBIAs are produced following a series of downstream biosynthetic modifications that lead to the introduction of additional functionality. Even so, and as noted by Weber and Opatz, the observed structural diversity of bisBIAs is not entirely substantiated by our current * Department of Chemistry, University of California, Riverside, California 92521, 8 United States understanding of their biosynthesis. For example, the See DOI: 10.1039/x0xx00000x 1 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins Figure 2. Current understanding of the bisBIA biosynthetic pathway. enzyme(s) responsible for the formation of sterically OC43) replication in MRC-5 human lung cells.22 Likewise, the encumbered, electron-rich diaryl ether bonds of cyclic bisBIAs approved bisBIA drug cepharanthine (11) was shown to inhibit such as tetrandrine (8) and berbamine (9) from berbamunine SARS-CoV-2 replication with minimal toxicity at a half maximal 11,12 (7) has not been identified. 23,24 effective concentration (EC50) of 0.35 µM (Figure 3). While the mechanism of action of cepharanthine (11) is multifaceted, 3. Biological activity the antiviral activity not only relies on suppression of nuclear factor-κB (NF-κB) signaling pathways but also induction of Bisbenzylisoquinoline alkaloids have drawn significant plasma membrane rigidity to hamper entry of the pathogen into attention due to their potent anti-inflammatory, antiviral, the cell.23 These activities highlight a new role for bisBIAs in the antitumor, analgesic and antiplasmodial properties.6 prevention and treatment of SARS-CoV-2 infection. Though Formulations containing these alkaloids have been used for many bisBIAs have yet to be biologically evaluated, some centuries as traditional medicines in India, China, sub-Saharan demonstrate potential as drug candidates and merit special Africa and Southeast Asia.13 Some active members even have emphasis: tetrandrine (8), berbamine (9), neferine (12), and the ability to immobilize skeletal muscle, hence their dauricine (13, Figure 3). pronounced use as arrow poisons in South America.14 While a detailed analysis of the pharmacology is beyond the 3.1 Tetrandrine scope of this review, the quantity of publications concerning the First isolated by Kondo and Tano in 1928, tetrandrine (8) is bioactivities of bisBIAs has largely increased. Several extensive the major bisBIA found in the roots of Stephania tetrandra studies have examined the antimicrobial and anti-allergenic (Menispermaceae), a climbing plant used in traditional Chinese characteristics of bisBIAs. The antiparasitic influence of twenty and Japanese medicine (Figure 3).25 Beyond its traditional use unique bisBIAs against Trypanosoma brucei and Leishmania for remedying autoimmune disorders, hypertension and donovani was explored by Camacho and co-workers.15 cardiovascular diseases, the pharmacological effects of Comparably, these alkaloids exhibited heightened synergistic tetrandrine have been the focus of various studies since the effects with the antibiotic cefazolin on methicillin-resistant late-1990s. The immunologic and vasodilatory properties of Staphylococcus aureus strains.16 tetrandrine have been well evaluated, particularly as a latent More recent findings have identified bisBIAs as inhibitors of therapeutic to treat drug-resistant autoimmune diseases and calcium influx in glial cells and neurons, combatting prevent excess fibrosis in patients with severe conjunctival neuroinflammation and neuroapoptosis.17 Another example by inflammation.26,27 Medeiros et al. reported that the alkaloid curine (10) induced The labs of Xu28 and Huang29 described the antiproliferative vasorelaxation via direct inhibition of L-type voltage-gated nature of tetrandrine (8) on human T and liver cancer cells, calcium current in rat aorta smooth muscle cells, triggering an respectively, by inhibition of NF-κB and calcium/calmodulin- intracellular decrease in transient calcium stores (Figure 3).18 dependent protein kinase II, both of which are critical regulators Of particular interest is the potential of these natural of not only innate immunity, but also cancer-related products as latent agents against the novel and highly inflammation. It was even found to upregulate in vitro pathogenic SARS-CoV-2, which is the fundamental cause of expression and activation of initiator and effector caspases in coronavirus disease 2019 (COVID-19). Plants of the glucocorticoid-resistant Jurkat T-cells, contributing to the Menispermaceae family are repeatedly used for the treatment apoptosis-inducing effect in T cell acute lymphoblastic leukemia of malaria as well as dengue fever and a number of isolated (T-ALL).26,30 alkaloids exert comparable antiviral consequences.19,20 He et al. Recently, the alkaloid has been recognized as an antagonist identified nine bisBIAs as potent in vitro SARS-CoV-2 entry of two-pore channels (TPC), or voltage-dependent calcium inhibitors.21 Tetrandrine (8) dramatically blocked viral S and N channels located on lysosomal membranes, which have been protein expression as well as human coronavirus OC43 (HCoV- 2 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins Journal Name ARTICLE suspected to be responsible for massive pulmonary edema and hemorrhage in mice models.39 Likewise, continuous administration of the alkaloid caused a marked pathological change in the liver tissues of dogs.40 3.2 Berbamine Berbamine (9) is a cyclic bisBIA isolated from the traditional Chinese herbal medicine Berberis amurensis (Figure 3).5 There is a well-documented history of its usage in clinical practice for treating inflammation, cancer, and